Leucemie acute mieloidi - Copyright FSE 1
Novità dall’EHA >> [ Leucemie acute mieloidi ]
27-28 ottobre 2008
Relatore: F. LO COCO
Borgo S. Luigi – Monteriggioni (Siena)
Leucemie acute mieloidi - Copyright FSE 2
Biologic & Clinical Studies Selection Criteria
� Not presented at ASH or considerable expansion of previously presented studies (updates, additional findings etc.)
� Unpublished, in press, or very recently published
2
� For biologic studies, emphasis on studies with potential impact into the clinics in the near future
� For clinical studies, emphasis on promising new agents (most likely to be further explored) and on randomised studies
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AML Biology : Overview (selection)
I. Basic studies
� Martelli et al: Silencing of NPM1 mut. by ATRA (# 17)
� Brundiers et al: miRNA in AML with different K (# 18)
� Iacobucci et al: DNA copy number analysis by SNPs (# 23)
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� Iacobucci et al: DNA copy number analysis by SNPs (# 23)
� Kronke et al: SNPs analysis in NK-AML (# 459)
� McLoman et al: c-FLIP as a regulator of cell survival (# 30)
� Hasan et al: Genomic analysis of t(15;17) in sAPL(# 944)
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AML Biology : Overview (selection)
II. Translational studies
� Chamuleau et al: INDO mRNA and AML outcome (# 20)
� Fiskus et al: Panobinostat + decitabine effect in vitro (#24)
� Maiso et al: Panobinostat + doxorubicin effect in vitro (# 33)
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� Maiso et al: Panobinostat + doxorubicin effect in vitro (# 33)
� Gaidzik et al: Prognostic impact of WT1 mut (adults # 943)
� Hollink et al: Prognostic impact of WT1 mut (children # 457)
� Cilloni et al: WT1 as an MRD marker (# 421)
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PROGNOSTIC IMPACT OF WT1 MUTATIONS IN THE CONTEXT OF
OTHER MOLECULAR MARKERS IN NK-AML: A STUDY OF THE
AMLSG (Gaidzik et al, # 943)
� Background: WT1 mutations reported in 10% NK-AMLSuggested negative impact on prognosisInfluence on other markers unknown
5
� Methods: Analyse impact of WT1 mutations in thecontext of NPM1, CEBPa, FLT3, RASmutations
602 pts with NK-AML, three AMLSG trials
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PROGNOSTIC IMPACT OF WT1 MUTATIONS IN THE CONTEXT OF
OTHER MOLECULAR MARKERS IN NK-AML: A STUDY OF THE
AMLSG (Gaidzik et al, # 943)
� Results: WT1 mutations in 12% Younger age, increased WBC Association with FLT3-ITD (P=.0008)and CBPA mut (P= .001)
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and CBPA mut (P= .001)
WT1mut alone no impact on prognosis WT1mut -FLT3-ITD worst prognosis
� Comments: WT1mut + FLT3-ITD potentially identifies RD
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WILMS’ TUMOR GENE MUTATIONS IN CHILDHOOD AML:
CHARACTERISTICS, PROGNOSTIC VALUE AND CONSEQUENCES
FOR MRD DETECTION (Hollink et al, #457)
� Background: Approximately 10% of adult AML with NK carry mutations in the WT1 gene. Suggested association with poor prognosis
7
� Methods: Screening of 298 diagnostic childhood AMLs using PCR-based direct sequencing. Paired dx.-rel. samples studied in 39 cases
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WILMS’ TUMOR GENE MUTATIONS IN CHILDHOOD AML:
CHARACTERISTICS, PROGNOSTIC VALUE AND CONSEQUENCES
FOR MRD DETECTION (Hollink et al, #457)
� Result: Mutations found in 35/298 (12%) Association with NK, FLT-ITD and high WBC Mutations gained at relapse in 4/28 (14%)Lower CR, OS and EFS
8
Lower CR, OS and EFS
� Comments: New relevant prognostic marker; problematic for MRD monitoring
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EARLY ASSESSMENT OF MRD BY OPTIMIZED REAL-TIME PCR FOR
DETECTION OF WT PROVIDES AN INDEPENDENT PREDICTOR OF
DFS IN AML (Cilloni et al, #421)
� Background: WT1 overexpressed in >90% AMLs Suitable “universal” MRD marker for AML
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� Methods: Comparison of sensitivity & specifitiy of 9 different R-Q-PCR assays 729 diagnostic & 106 f-up samples11 European labs (LeukemiaNet)
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EARLY ASSESSMENT OF MRD BY OPTIMIZED REAL-TIME PCR FOR
DETECTION OF WT PROVIDES AN INDEPENDENT PREDICTOR OF
DFS IN AML (Cilloni et al, #421)
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� Result: Failure to normalize WT1 transcripts post-ind.correlates with relapse in 100% of cases (independent predictive factor)
Decreased levels post-treatment non fullyinformative on outcome
� Comments: Important EARLY information, most relevant (if confirmed) to adjust post-induction therapy
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AMONAFIDE: A TOPO II INHIBITOR WITH NOVEL
PHARMACOLOGICAL PROPERTIES AND UNIQUE ACTIVITY FOR THE
TREATMENT OF SEC. AML (Capizzi et al, #890)
Background:
Secondary AML (sAML) portends a poor prognosis due to disease
and patient-related factors. Newer therapies are needed.
11
Aims:
� Comparison of amonafide to classical TOPO II inhibitors(anthracyclines, mitoxantrone, etoposide)
� Efflux from patient-derived sAML blasts
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AMONAFIDE: A TOPO II INHIBITOR WITH NOVEL
PHARMACOLOGICAL PROPERTIES AND UNIQUE ACTIVITY FOR THE
TREATMENT OF SEC. AML (Capizzi et al, #890)
� combination of amonafide (600mg/m2/day1-5 and ara-C, 200 mg/m2/day 1-7 c.i.)
� 88 sAML patients
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� 88 sAML patients
� Median age 63 yrs (range 23-87)
� prior MDS: 45.5%; t-AML: 54.5%
� unfavorable cytogenetics: 47%
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Results (I)
13
10
15
20
Amonafide
� Amonafide had equal cytotoxicity in both the wild type
and MDR cells.
� Additional studies showed that amonafide was neither
a substrate nor an inhibitor of Pgp.
0
5
E F F L UX E F F L UX
in unf. K
E F F L UX
in C R
DNR
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Results (II)
14
� Median CR duration : 10 mos.
� CCR at 12 mos: 44%
� Death within 28 days: 20%
� Marrow recovery: 1 mo.
� 6% moderate diarrhea and skin
rash
*: azacytidin
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A DOUBLE BLIND PLACEBO-CONTROLLED RANDOMIZED PHASE III
STUDY OF HIGH DOSE CONTINUOUS INFUSION ARAC WITH OR
WITHOUT CLORETAZINE IN FIRST RELAPSE AML (Norbert et al, #35)
� VNP40101M is a novel alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links and which showed anti-leukemic activity in clinical trials.
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� Multi-center phase III study to compare overall response rate (CR,CRp,safety of VNP40101M + araC vs placebo + araC, in patients with AML in first relapse.
� Secondary endpoints were response duration, progression-free and overall survival (OS).
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A DOUBLE BLIND PLACEBO-CONTROLLED RANDOMIZED PHASE III
STUDY OF HIGH DOSE CONTINUOUS INFUSION ARAC WITH OR
WITHOUT CLORETAZINE IN FIRST RELAPSE AML (Norbert et al, #35)
� ≥18 yrs, and in first relapse after CR1 of 3-24 mos.
� Randomized (2:1) to ara-C 1.5 g/m2 (d1-3)+ VNP40101M 600 mg/m2, or ara-C 1.5 g/m2 (d1-3) + placebo.
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mg/m2, or ara-C 1.5 g/m2 (d1-3) + placebo.
� Patients with at least 20% blast reduction in the bone marrow could receive a second induction.
� Patients with CR or CRp could be consolidated according to original randomization, but at a lower dose of VNP40101M (400 mg/m2) or placebo.
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A DOUBLE BLIND PLACEBO-CONTROLLED RANDOMIZED PHASE III
STUDY OF HIGH DOSE CONTINUOUS INFUSION ARAC WITH OR
WITHOUT CLORETAZINE IN FIRST RELAPSE AML (Norbert et al, #35)
� Median age for 210 patients was 59 yrs;
� 63% patients had CR1 <12
17
150
200
Controls VPN+ARAC
� 63% patients had CR1 <12 months (median 290 days).
0
50
100
ORR Surv
(days)
Death rate
67% of treatment group deaths were due to infection, sepsis, or pneumonia.
18% to pulmonary events (8/10 ARDS)
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PHASE II STUDY OF SINGLE AGENT CLOFARABINE IN UNTREATED
ELDERLY PATIENTS WITH AML UNLIKELY TO BENEFIT FROM
STANDARD INDUCTION CHEMOTHERAPY (Erba et al, #892)
� Phase II, open-label, single arm
� Multicenter, conducted in North America
18
� 26 sites eligible to enroll
� 20 sites enrolled patients
� Median number per site 4; range 1-26
� First patient registration: 27 October 2006
� Last patient registration: 27 November 2007
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PHASE II STUDY OF SINGLE AGENT CLOFARABINE IN UNTREATED
ELDERLY PATIENTS WITH AML UNLIKELY TO BENEFIT FROM
STANDARD INDUCTION CHEMOTHERAPY (Erba et al, #892)
� AML (de novo or secondary) according to WHO
� Age ≥ 60 years
19
� ECOG performance status (PS) 0-2 and adequate renal, hepatic, and cardiac function
� At least 1 of the following adverse prognostic factors:
� Age ≥ 70 years
� ECOG PS 2
� Antecedent hematologic disorder (AHD)
� Intermediate- or unfavorable-risk blast karyotype
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PHASE II STUDY OF SINGLE AGENT CLOFARABINE IN UNTREATED
ELDERLY PATIENTS WITH AML UNLIKELY TO BENEFIT FROM
STANDARD INDUCTION CHEMOTHERAPY (Erba et al, #892)
20
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PHASE II STUDY OF SINGLE AGENT CLOFARABINE IN UNTREATED
ELDERLY PATIENTS WITH AML UNLIKELY TO BENEFIT FROM
STANDARD INDUCTION CHEMOTHERAPY (Erba et al, #892)
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RESPONSE
CATEGORY
ORR (CR + CRp)
CR
RESPONSE
RATE (95% CI)
45.2% (35.9%, 54.8%)
40.0% (31.0%, 49.5%)CR
CRp
Failure
Unknown
40.0% (31.0%, 49.5%)
5.2% (1.9%, 11.0%)
53.0% (43.5%, 62.4%)
2
• Remissions (CR + CRp) after cycles 1 and 2 of therapy (N=52):
� 35/52 remissions after cycle 1 (induction)
� 17/52 remissions after cycle 2 (re-induction)
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Overall Remission Rates (ORR) by Baseline
Prognostic Factors (Investigator-assessed, N=113)*
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Number of Risk
Factors
Patients
in SubsetCR + CRp (n) CR + CRp (%)
1
2
3
4
22
50
38
1
11
24
16
0
50%
48%
42%
0%
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Overall Remission Rates (ORR) by Baseline
Prognostic Factors (Investigator-assessed, N=113)*
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Prognostic Factor Patients in
SubsetCR + CRp (n) CR + CRp (%)
AgeAge
> 70
< 70
70
43
28
24
40%
56%
Performance Status
ECOG 2
ECOG 0-1
26
87
10
42
38%
48%
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Overall Remission Rates (ORR) by Baseline
Prognostic Factors (Investigator-assessed, N=113)*
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Prognostic Factor Patients in
Subset
CR + CRp
(n)
CR + CRp
(%)
Presence of AHD
Yes 42 50%21
No
Unknown
66
5
102
46
56
0
11
44%
40%
Cytogenetics
Intermediate/Unfavorable
Intermediate
Unfavorable
Favorable
Not reported
29
2
48
24
24
--
4
47%
52%
43%
--
36%
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Adverse Events (%)
25
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CLO243: Conclusions
� ORR :45% (CR 40%; 1/3 after 2 cycles)
� RR not affected by adverse risk factors such as age over 70, PS 2, AHD, and unfavorable K.
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� All-cause 30-day mortality: 9.6%.
� Clofarabine is active with acceptable toxicity in a poor risk population of older AML pts unlikely to benefit from standard induction chemotherapy.
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